Macrophages as targets for adoptive cell therapy against solid tumors

Macrophages as targets for adoptive cell therapy against solid tumors | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 15 October 2025 V1 Latest version Share on Macrophages as targets for adoptive cell therapy against solid tumors Author : Rafael Cardoso Maciel Costa Silva 0000-0002-0877-273X [email protected] Authors Info & Affiliations https://doi.org/10.22541/au.176051559.98733640/v1 134 views 97 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract The ability to modulate the tumor microenvironment emerges as a compelling strategy to stimulate antitumor immunity in solid tumors. In this context, innate immune cells, especially macrophages, are interesting targets for immunotherapies. Approaches, based on CRISPR, to delete specific suppressive molecules in these cells might lead to antitumor immunity depending on the type of tumors, since their tumor microenvironment can be diverse. This correspondence aims to discuss published animal models and stimulate research in this critical subject for the improvement of immunotherapies aiming on macrophages. New therapeutic strategies, including epigenetic modifications to stabilize the proinflammatory phenotypes of these cells, are underscored. Macrophages as targets for adoptive cell therapy against solid tumors Rafael Cardoso Maciel Costa Silva 1 1 Faculty of Medical Sciences, State University of Rio de Janeiro, Cabo Frio, Brazil *Corresponding author: [email protected] Abstract The ability to modulate the tumor microenvironment emerges as a compelling strategy to stimulate antitumor immunity in solid tumors. In this context, innate immune cells, especially macrophages, are interesting targets for immunotherapies. Approaches, based on CRISPR, to delete specific suppressive molecules in these cells might lead to antitumor immunity depending on the type of tumors, since their tumor microenvironment can be diverse. This correspondence aims to discuss published animal models and stimulate research in this critical subject for the improvement of immunotherapies aiming on macrophages. New therapeutic strategies, including epigenetic modifications to stabilize the proinflammatory phenotypes of these cells, are underscored. Short communication The development of cancer immunotherapy was groundbreaking for the treatment of some aggressive tumors, offering hope to patients for which other therapies were inefficient. Despite this, immunotherapy still needs to be improved, and solid tumors with their heterogeneous and suppressive microenvironment (TME), are a big challenge to overcome. In this context, TME modulation after injection of Bacillus Calmette Guérin (BCG) can promote antitumor immunity in bladder cancer patients and murine mouse models [1]. However, in other cold solid tumors, which are characterized by low mutational burden and reduced infiltration of immune cells (like T cells and dendritic cells), immunotherapies are usually ineffective [2]. In general, cancer immunoediting contributes to the emergence of tumors that lack the complex MHCs-neoantigens that bind T cell receptors (TCRs), leading to tumor masses that escape immune recognition. Cold tumors are also characterized by the secretion of suppressive molecules and/or expression of inhibitory receptors by tumor cells and infiltrated immune cells, like regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). The presence of a dense extracellular matrix (ECM) can also be found in some tumors, restricting in a physical way the infiltration of effector immune cells. As a manner to circumvent these suppressive features that restrain antitumor immunity, adoptive cell transfer is an interesting strategy, bypassing the necessity of previously activated immune cells in the TME. A great deal of preclinical and clinical trials uses engineered T cells for adoptive transfer, expressing chimeric antigen receptors (CARs) that react specifically against surface antigens in tumor cells. Here, I would like to highlight the findings that support the development of adoptive cell therapies aimed at innate immune cells. In my opinion, the infusion of innate immune cells, especially myeloid cells, like macrophages, might be particularly interesting due to their ability to modulate the TME, mediating antitumor immunity [3; 4]. In this sense, the presence of innate immune cells, like peritoneal macrophages [3] and polymorphonucleated granulocytes [3], but not T cells, is critical for the transfer of cancer resistance from spontaneous regression/complete resistance mice to susceptible ones [4]. Another aspect is that the deletion of genes involved in the suppression, or in the suppressive role of macrophages by CRISPR might promote antitumor immunity in a much simpler manner than inserting and monitoring the expression of CARs [5]. Recently, in a preclinical mouse model, the transfer of macrophages epigenetically repressed for the expression of HIF-1α, led to antitumor immunity [5]. Thus, the in vitro generation of antitumor inflammatory (M1)-differentiated macrophages deleted in specific genes according to the TMEs of distinct tumors, rendering these macrophages resistant to silencing molecules of this particular TME, would be a general strategy to treat specific solid tumors that share similar TMEs or common negative modulators of immune responses. M1 macrophages possess increased antigen-presenting ability and a proinflammatory role, secreting IL-12 that promotes CD8+ T cells, NK cells and Th1 cells’ function. In addition, M1 macrophages also liberate cytotoxic molecules, like nitric oxide and reactive oxygen species that can lead to tissue/tumor damage [6]. Another approach recently described to promote antitumor immunity after TME change was to treat antigen-pulsed macrophages with a combination of cytokines (Tumor necrosis factor and interferon gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), agonists of costimulatory molecules (anti-CD40) and agonists of pattern recognition receptors (PRRs) (polyinosinic-polycytidylic acid, a Toll-like receptor 3 agonist) before infusing these hyperactivated macrophages in a tumor mouse model (breast cancer cell line) [7]. Importantly, TMEs and their silencing molecules are diverse and tumor cells can secrete and respond to cytokines, chemokines and other molecules involved in immune responses. Therefore, alternatively-activated(M2)-macrophages might also be used to treat some specific tumors. For example, M2 macrophages promote myeloma elimination after the depletion of arginine, leading to starvation of these specific tumor cells [8], despite the fact that arginine depletion can also suppress immune responses. In this specific context, the negative effect of arginine depletion in tumor cells is more important for tumor elimination than its deleterious effect in immune cells and consequently antitumor immunity. M2 macrophages also possess high phagocytic capability but, in general, are considered protumors, possessing poor antigen-presenting capability and promoting wound-healing, which restrains tissue (tumor) damage [6; 9]. In summary, distinct preparations of deleted and stimulated in vitro macrophages can be made to eliminate different tumors (Figure 1). Furthermore, peripheral blood monocytes (i) can be easily manipulated in vitro, (ii) are abundantly present in the peripheral blood and (iii) do not proliferate as much and lead to uncontrolled immune responses compared to T cells. In this context, some important checkpoint receptors or transcription factors of macrophages have been described to restrain antitumor immune responses, like Siglec-10, SIRPα, Mertk, LILRBs, TREM1, TREM2 and ZEB2, being interesting molecular targets for antagonism, as described by others [10-16]. To complement this strategy, trained immunity (or epigenetic modulation by pharmaceuticals) can be used as a tool to “stabilize” the proinflammatory role of the infused macrophages and restrain the suppressive effect of distinct molecules in the TME. Furthermore, inflammasome assembly and type I interferons can promote hyperactivated innate immune cells, especially dendritic cells with higher antigen presentation capability [17] and macrophages [18]. Both techniques can be used to generate hyperactivated myeloid cells in vitro for in vivo infusion. Thus, peripheral blood monocytes can be genetically and epigenetically manipulated before being activated by PRRs agonists and infused in tumors to promote antitumor immunity, according to the TME of this specific type of tumor. These clues can be obtained by omics, (i) classifying tumors according to the presence of common suppressive molecules in the TME by metabolomics and proteomics; (ii) or through the use of public transcriptomic data for the correlation of overall survival and the expression of certain immunomodulatory genes in distinct tumor samples after Kaplan-Meier analysis. Combinatory therapies with infusion of macrophages and T cells can also be pursued, as both cells can collaborate with each other to promote antitumor immunity [19; 20]. Furthermore, FDA-approved pharmaceuticals that modulate molecules involved in the immune suppressive role of TMEs, can also be applied, as a manner to further improve immunotherapy. For instance, hydralazine and epacadostat inhibit amino oxidase 3 and indoleamine dioxygenase 1, respectively, and can be used to prevent methylglyoxal and kynurenine generation and subsequent immunosuppressive effects in distinct tumors [21; 22]. The development of other pharmaceuticals, biological or chemical, can further improve current immunotherapies. For instance, the development of specific agonistic or antagonistic monoclonal antibodies [23]; anti-sense nucleotides [24]; or synthetic peptides/molecules can lead to compelling target therapies [25]. Finally, macrophages infusion can also be made both systemically (intravenously) or intratumor. Systemic administration of macrophages might need the (genetically induced) expression of chemokine receptors, according to the presence of chemokines within tumors, assessed by transcriptomic and/or proteomic studies of each tumor type. The adoptive transfer of macrophages as a therapy against liver cirrhosis in humans is under clinical trials [26], reinforcing that this cellular therapy is a compelling treatment strategy to be pursued in other diseases as well, including tumors. Figure 1: Different macrophages preparation can be used to promote antitumor immunity against distinct tumors. Solid tumors possess distinct metabolic requirements and express and secrete different anti-inflammatory mediators that contribute to a suppressive TME. Characterization of tumors by omics according to their suppressive TME can lead to the development of specific macrophages that aim to eliminate these tumors. In this context, CD47-expressing tumor cells can be eliminated by highly inflammatory trained M1-like macrophages deleted of SIRPα, the inhibitory receptor that binds CD47 (A). On the other hand, arginine depletion by M2 macrophages deleted from LILRB, can lead to the elimination of tumors that require arginine for their metabolism and escape immune responses through the expression of HLA-G (B). Keywords: Tumor immunotherapy; innate immunity; macrophages; tumor microenvironment DECLARATION Funding: I acknowledge the financial support of Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior- CAPES; Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro- FAPERJ E-26/200.628/2022. Conflicts of interest/ Competing interests: None Ethics approval: Not applicable Consent to participate: Not applicable Written consent for publication: Not applicable Availability of data and materials: Not applicable Code availability: Not applicable Author’s contribution: Silva RCMC was responsible for the conceptualization and wrote the manuscript Declaration of Generative AI and AI-assisted technologies in the writing process: Statement: During the preparation of this work the author, Rafael Cardoso Maciel Costa Silva, did not use any generative AI and AI-assisted technologies in the writing process. The author takes full responsibility for the content of the publication. References: 1. Atallah A, Grossman A, Nauman RW, Paré JF, Khan A, Siemens DR, Cotechini T, Graham CH. Systemic versus localized Bacillus Calmette Guérin immunotherapy of bladder cancer promotes an anti-tumoral microenvironment: Novel role of trained immunity. 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Supplementary Material File (image1.emf) Download 101.69 KB Information & Authors Information Version history V1 Version 1 15 October 2025 Copyright This work is licensed under a Non Exclusive No Reuse License. Keywords innate immunity macrophages tumor immunotherapy tumor microenvironment Authors Affiliations Rafael Cardoso Maciel Costa Silva 0000-0002-0877-273X [email protected] Universidade do Estado do Rio de Janeiro Faculdade de Ciencias Medicas View all articles by this author Metrics & Citations Metrics Article Usage 134 views 97 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Rafael Cardoso Maciel Costa Silva. Macrophages as targets for adoptive cell therapy against solid tumors. Authorea . 15 October 2025. DOI: https://doi.org/10.22541/au.176051559.98733640/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. 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